You may have been approached by one of your patients to discuss the issue of
Targeted Nutritional Intervention and the use of Piracetam in Down syndrome.
You may have, in most cases, drawn a blank or have self-referred back to the
era of mega-vitamin therapy and drawn an immediate negative reaction. What
is all of this and does it have any grounding in medical science or is it
nothing but snake oil?

First of all, it isn't snake oil. The TNI formulation, NuTriVene-D, was
designed originally by Dixie Lawrence Tafoya. All subsequent modifications
were based on journal articles or research and reviewed and approved by the
SAC (Scientific Advisory Committee) of Trisomy 21 Research Foundation, Inc.
(TRI). Dixie Tafoya first developed this formula based on the work of Henry
Turkel, M.D. carried out from the 1940s to the 1970s in which he used a
formulation based on some educated guesses. These guesses were made without
benefit of formal knowledge of the biochemistry or genetics of Trisomy 21.
In fact, when Dr. Turkel first developed his formula, the correct number of
human chromosomes was not known nor was it known that Down syndrome was
produced by an extra chromosome 21. Today, the ongoing Genome Project in
association with improved metabolic assaying techniques has afforded us a
better view of the genetics and biochemistry of chromosome 21 in order to
make more accurate estimations of what supplementation may help in the
treatment of Trisomy 21.

Gene Overexpression in Trisomy 21

Most recent gene mapping has sequence all of the genes on chromosome 21
This doesn't mean that they are all known, that process will take more time.
But within a few years we should know all of the genes and their protein products.
Already several gene families of developmental genes have been found. Some of
these because they are turned on only prenatally cannot be influenced but some of
them may be amenable to either metabolic or gene therapy in the future. This is
exciting new work and has the potential for many new therapies but in the meantime
what can be done?

Arguments have been made both pro and con for treating Trisomy 21 as a
disease. It is unreasonable to expect that the genes that are present on the
additional chromosome 21 are non-functional. In fact, gene dosage studies
have shown for many years that many of the genes on 21 are quite functional
and producing 40-50% increases of their gene products. Two of these,
zinc/copper superoxide dismutase and cystathionine beta synthase are major
sources of concern in Trisomy 21. Obviously genes that are developmental in
nature such as DYRK and are only turned on in fetal life cannot be affected
by any therapy that is begun postnatally but sufficient genes are active to
cause a mix of biochemical problems in Trisomy 21.

Is there evidence of metabolic abnormalities in DS? Yes, numerous studies
(see Bibliography below) have demonstrated biochemical abnormalities in DS.
The first to find these was Jerome LeJeune, who is the physician who first
discovered Trisomy 21 as the basis of Down syndrome. LeJeune found that
single carbon chains were handled abnormally by people with Down syndrome.
This, we now know, is caused by disruptions in the S-Adenosylmethionine
cycle or SAM cycle mediated by the enzyme cystathionine beta synthase which
is on chromosome 21. The result of these abnormalities is an increased
cysteine pool, loss of homocysteine and and decreased methyl groups
available for DNA methylation and other biomethylations. Secondary to this
is a disruption of folic acid metabolism caused by trapping of folate as
5-methyltetrahydrofolate. LeJeune later demonstrated abnormalities in
purine synthesis that produces high levels of uric acid, presumably caused
by the gene GART (first 3 steps in purine synthesis) which is also
triplicated.

The zinc/copper enzyme Super Oxide Dismutase (SOD) is well known to be
over-functioning in Trisomy 21. It normally is the first step in metabolic
conversion of superoxide. Superoxide is a free radical that may cause
problems to both the cell membrane and the cell nucleus. SOD produces
hydrogen peroxide which two other (not on chromosome 21) gene products,
catalase and glutathione peroxidase, convert to nontoxic products. Neither
catalase nor glutathione peroxidase are sufficiently upregulated to handle
the excess hydrogen peroxide. Hydrogen peroxide is a potent oxidizer which
on the cell surface produces lipid peroxidation and compromises the cell
membrane, particularly in the presence of excess iron (Fenton reaction). At
the organelle and nuclear level, hydrogen peroxide causes damage and
stimulates apoptosis ("programmed" death) of the cell. In a study by de Haan
et al in Human Molecular Genetics (5:283-292, 1996), it was found that the
ratio of SOD to glutathione peroxidase led to increased hydrogen peroxide in
the cells and cellular senescence. In a study from Nature (1995), Busciglio
and Yankner demonstrated that fetal neuronal cells from non-DS and DS
fetuses grew differently. The non-DS cells grew in culture in an orderly
fashion but the DS cells grew for only 72 hours and began dying. When a
second DS culture was incubated with powerful antioxidants these cells began
growing normally. While not direct evidence of the role of reactive oxygen
species in the production of symptomotology of DS it certainly provides
useful information and a starting place for future studies. This is the
logic behind using additional antioxidants in DS.

A recent paper by G. Lubec (2002) J. Neurol. 249: 1347-1356 proposes that molecular evidence of the role of reactive oxygen species and apoptosis of brain cells exists. This evidence is strong and points to antioxident treatment as a means of preventing future damage.

Immune Dysfunction
Numerous studies have documented immune dysfunction in Down syndrome
including decreased IGA, low white cell counts, and low levels of T-cells.
These deficits probably lead to the increased incidence of upper
respiratory, ear, and gastrointestinal infection rate in Down syndrome most
evident in children but even present in adults. The immune dysfunction seems
to be related to zinc depletion but also may be an indirect result of the
effects of hydrogen peroxide on immune cells. TNI seems to directly impact
this parameter and significant improvement in the incidence of infections is
one of the primary effects of TNI.

Growth
It has always been assumed that children and adults with Down syndrome will
be short. This seems to be a case of self-fulfilling prophecy. Children who
are supplemented throughout their lives show a significant increase in
growth velocity. In addition, many studies demonstrate an increased
incidence of growth hormone deficiency in this population. Looking for and
treating growth hormone deficiency may also go towards increasing height in
this population. In fact, endocrine dysfunction is not uncommon in Down
syndrome. Certainly the connection with hypothyroidism as well as
infertility in males with Down syndrome is well known.

Lipid Handling
Numerous studies have shown poor lipid metabolism in Down syndrome. Omega 3
and 6 fatty acids (ALA, AA) are decreased. Cholesterol is often increased
without a concomitant increase in cardiovascular risk. Apolipoproteins
E is abnormal and may contribute to the increased Alzheimer risk in
Down syndrome. While DHA (docosohexaenoic acid) is not specifically
decreased in Down syndrome it is normally low in the diets of nonbreast-fed
and American-diet breast-fed infants and children. There is good data to
show improvements in brain and retinal development in children supplemented
with DHA. DHA has been added to infant formulas in Europe and is currently
under consideration for a similar use in the US.

Alzheimer Disease
The risk for the development of Alzheimer disease in Down syndrome has been
estimated as high as 40%. While these figures are hard to demonstrate, the
risk is definitely both increased and also at an earlier age of onset. This
does not necessarily translate into clinical symptoms. Alzheimer disease
risk in Down syndrome is not related to any one factor but a host of factors
including a gene for Alzheimer disease on chromosome 21, lipid handling
abnormalities, increased hydrogen peroxide damage to the cells, endocrine
abnormalities and reduced acetylcholine receptors in the brain. Current
estimates are that over 50% of adults with Down syndrome will develop MRI
evidence of Alzheimer disease by age 45.

General Principles of TNI

TNI is not a cure for Down syndrome. It is a treatment plan that provides
additional nutrients and micro nutrients to promote:

Growth

Improved health status

Improved immune function

Cognitive enhancement

Prevention or amelioration of long term degeneration and disability.

Does it work? I have been observing patients for the last 7 years who were
on this protocol as well as patients not on this protocol. A cohort study
has been assembled consisting of 200 patients ranging from 1 month to 4
years of age, and a control group (all on multivitamins) has been followed
consisting of 200 patients, ranging from 1 month to 4 years of age.
Comparable figures for the two groups were noted for the incidence of
congenital heart disease, cardiac surgery, hypothyroidism, day care or
school attendance, breast feeding, sex, and race. These observations are
subject to the bias that they were not blinded for investigator, patients or
parents but still have validity.

Piracetam, one of a growing group of drugs known as nootropics (which means
acting on the mind) is an important part of the TNI protocol. This drug has
been used extensively in Europe and Russia originally for the treatment of
Alzheimer disease but eventually in the late 1970s in Spain, Italy and
Germany for the treatment of Down syndrome. A double-blind study published in 2001 by Lobough et al was a small study with serious methodological flaws. George Capone, M.D. at Johns Hopkins Kennedy Krieger Institute is doing ongoing research into the use of Piracetam. The only known study to date in Down
syndrome was an unblinded study from Spain in 1978 that showed improvement
in academic performance while taking Piracetam. No serious side-effects were
seen and no serious side effects are reported in the very extensive
literature that exists for Piracetam. In fact, the LD-50 for Piracetam in
laboratory animals requires an IV dose of 8-10 gms/kg, and no oral LD-50 has
been reported. The side-effects seen may include headache, gastrointestinal
disturbance, fine papular rashes that are transient, and occasionally
hyperactivity in children who already show some tendency towards
hyperactivity.

Its action in Down syndrome is two-fold. One aspect is the return of
membrane fluidity to cell membranes that have undergone lipid peroxidation.
Lipid peroxidation is known to be significantly higher in Down syndrome and
Alzheimer disease. This lack of fluidity tends to decrease signal intensity
in neurons and actually decreases ion flow in and out of cells and thus
decreases signal propagation as well. A second effect is the increase in
acetylcholine receptors. Acetylcholine receptors have been shown to be
decreased in both Down syndrome and Alzheimer disease. Piracetam has been
shown by experimental studies to be most active in the corpus callosum of
the brain. While no study has shown corpus callosum deficits in the brain of
persons with Down syndrome it is an area that is susceptible to lipid
peroxidation as is the basal ganglia and hippocampus. Piracetam seems to
have its greatest effect in speech production and visual motor
coordination/learning.

Piracetam may be prescribed under the Orphan Drug act. It is approved for
use in progressive myoclonic epilepsy but to date not for Down syndrome.
This, however, is not unusual for Pediatric drugs most of which have never
been double-blind tested in children and most of which do not have Pediatric
indications. Most pharmacies do not carry it but compounding pharmacies are
allowed to make it from base ingredients. It can also be purchased from
England or Mexico.

In addition, newer forms of Piracetam such as Pramacetam are coming on the market
and may show more efficacy than Piracetam. Alzheimer medications such as Aricept
(Donapezil) and Exelon (Rivastigmine) are currently or have been studied with promising
results in cognitive improvement and behavior in the preteen, adolescent, and adult groups.

The Nutrivene D Formula

(Disclaimer: Neither I nor any member of the Scientific Advisory Committee
of Trisomy 21 Research Foundation, Inc. has, to my knowledge, any financial
interest in International Nutrition or any of the products listed below.)

Nutrivene-D can be obtained from International Nutrition, Inc., by calling
1-800-899-3413. Dosage is by weight. Person over 16 years of age should
request the adult formula. The package comes with 3 bottles: Daily formula,
Enzyme capsules and Night-time formula. You can mix up the first two with
the piracetam in the morning and give the 3 daily doses that way. The enzyme
formula is the one part that can cause problems. If diarrhea occurs stop
enzyme and restart with smallest amount you can give and work up to
prescribed dose. If diarrhea restarts go back to last dosage without
diarrhea. Do not give night-time formula less than 1 hour from bed time. Do
night give night time formula closer than 2 hours from last daily
supplement. If reflux develops stop the daily enzyme and call International
Nutrition.

Why do I use NuTriVene-D and not other supplements for my patients? The
Scientific Advisory Committee of Trisomy 21 Research Foundation, Inc.
controls what goes into the formulation. Nothing can be added or subtracted
without its approval. It is produced in an FDA-inspected facility under
infant formula guidelines and good manufacturing practice (GMP) guidelines.

Piracetam is given at 75 mg/kg body weight/day. Dosage will need to be
increased every 10 lb. of weight. The Piracetam prescription can be faxed to
Hazle Drugs in Hazleton, Pennsylvania. They will call you to activate the
prescription. The voice phone number for Hazle Drugs is 1-800-439-2026 (ask
for Bill Spears, Jr.). Prescriptions can also be faxed to International Nutrition at 410-902-1767.

Efamol or Evening Primrose Oil should be given to augment essential fatty acids. It is available
from International Nutrition at 1-800-899-3413. The dosage is 2 capsules
per day for children under the age of 5 or 4 capsules per day for children
age 5 and older. Split them up during the day. This comes in a liquid form as well.

DHA daily as Neuromins brand from International Nutrition. Open with pin
and squeeze out. The dosage 1 capsule per day up to 5 years then 2 capsules
per day. DHA now comes a chewable form as well.

All children with Down syndrome should be given the following immunizations:

Influenza vaccine yearly after one year of age.

Acellular Pertussis(Whooping cough) with the DTP will now be listed as
DTaP. Give HIB separately not conjugated.

Varivax(Chickenpox) vaccine between 1 and 2 years of age.

Prevnar in all children. See new Redbook recommendations.

All polio vaccine should be IPV (old Salk variety) and not OPV.

Measles, mumps, and rubella given by itself.

Laboratory Tests:

CBC every 6 months until 6 years of age. (Looking for leukemia)

T3, T4 and TSH every year for life. (Thyroid testing)

Atlantoaxial X-rays at 2 years of age especially in active children. (Looking for atlantoaxial dislocation)

Medications to avoid include sulfa-containing antibiotics (Pediazole,
Gantrisin, Septra, Bactrim). Sulfa drugs can further deplete zinc in
zinc-depleted children. If sulfa drugs must be used, then an additional 10
mg a day of zinc should be supplemented while the child is taking the sulfa
drugs. Do not give the child additional vitamins without first checking with
us. Do not give the child additional iron unless the child has proven iron
deficiency anemia. Iron increases the Fenton reaction and thus lipid
peroxidation. Additionally, excess iron is often stored in the brain and may
contribute to long-term CNS dysfunction.

Anneren G, Erdman B. Down syndrome -- a gene dosage disease caused by
trisomy of genes within a small segment of the long arm of chromosome 21,
exemplified by the study of the effects from the superoxide-dismutase type 1
(SOD1) gene. APMIS 1993; 40 Supp:71-79.(abstract)

Geggei RL, O'Brien JE, Feingold MF. Development of valve dysfunction in
adolescents and young adults with Down syndrome and no known congenital
heart disease. Journal of Pediatrics 1993; 122:5:1:821-823.